US2017368189A1PendingUtilityA1
Cnp prodrugs
Assignee: ASCENDIS PHARMA GROWTH DISORDERS ASPriority: Jan 9, 2015Filed: Jan 8, 2016Published: Dec 28, 2017
Est. expiryJan 9, 2035(~8.5 yrs left)· nominal 20-yr term from priority
Inventors:Kennett SprogøeUlrich HerselHarald RauThomas WeggeFrank FaltingerFelix CleemannNora KaluzaAna BernhardAnnette BubaTom Woods
A61P 5/10A61P 43/00A61P 27/02A61P 19/00A61P 25/00A61P 17/00A61P 19/02A61P 1/02A61P 19/08A61K 9/0019A61K 38/2242A61K 38/22A61K 38/1709A61K 47/60
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Claims
Abstract
The present invention relates to prodrugs of C-type natriuretic peptide (CNP), pharmaceutical compositions comprising such CNP prodrugs and their uses. In an embodiment, the CNP prodrugs are conjugates of CNP peptides to poly(ethylene glycol) through a reversible linker.
Claims
exact text as granted — not AI-modified1 . A CNP prodrug or a pharmaceutically acceptable salt thereof, wherein the prodrug is of formula (Ia) or (Ib)
wherein
-D is a CNP moiety;
-L 1 - is a reversible prodrug linker moiety;
-L 2 - is a single chemical bond or a spacer moiety;
—Z is a water-soluble carrier moiety;
x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16; and
y is an integer selected from the group consisting of 1, 2, 3, 4 and 5.
2 . A CNP prodrug or a pharmaceutically acceptable salt thereof comprising a conjugate D-L, wherein
-D is a CNP moiety; and -L comprises a reversible prodrug linker moiety -L 1 -; wherein -L 1 - is substituted with -L 2 -Z′ and is optionally further substituted; wherein -L 2 - is a single chemical bond or a spacer moiety; and —Z′ is a water-insoluble carrier moiety.
3 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 2 , wherein —Z′ is a hydrogel.
4 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the CNP prodrug is of formula (Ia).
5 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein x is 1.
6 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein CNP moiety has the sequence of SEQ ID NO:25 or SEQ ID NO:24.
7 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the CNP moiety has the sequence of SEQ ID NO:24.
8 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein -L 1 - is conjugated to the side chain of an amino acid residue of the ring moiety of -D or to the backbone of the ring moiety of -D.
9 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein -L 1 - is conjugated to the side chain of an amino acid residue of the ring moiety of -D selected from the group consisting of histidine, lysine, tryptophan, serine, threonine, tyrosine, aspartic acid, glutamic acid and arginine.
10 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein -D has the sequence of SEQ ID NO:24 and -L 1 - is conjugated to the lysine at position 26 of -D.
11 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the moiety -L 1 - is of formula (II):
wherein the dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond;
—X— is —C(R 4 R 4a )—; —N(R 4 )—; —O—; —C(R 4 R 4a )—C(R 5 R 5a )—; —C(R 5 R 5a )—C(R 4 R 4a )—; —C(R 4 R 4a )—N(R 6 )—; —N(R 6 )—C(R 4 R 4a )—; —C(R 4 R 4a )—O—; —O—C(R 4 R 4a )—; or —C(R 7 R 7a )—;
X 1 is C; or S(O);
—X 2 — is —C(R 8 R 8a )—; or —C(R 8 R 8a )—C(R 9 R 9a )—;
═X 3 is ═O; ═S; or ═N—CN;
—R 1 , —R 1a , —R 2 , —R 2a , —R 4 , —R 4a , —R 5 , —R 5a , —R 6 , —R 8 , —R 8a , —R 9 , —R 9a are independently selected from the group consisting of —H; and C 1-6 alkyl;
—R 3 , —R 3a are independently selected from the group consisting of —H; and C 1-6 alkyl, provided that in case one of —R 3 , —R 3a or both are other than —H they are connected to N to which they are attached through an SP 3 -hybridized carbon atom;
—R 7 is —N(R 10 R 10a ); or —NR 10 —(C═O)—R 11 ;
—R 7a , —R 10 , —R 10a , —R 11 are independently of each other —H; or C 1-6 alkyl;
optionally, one or more of the pairs —R 1a /—R 4a , —R 1a /—R 5a , —R 1a /—R 7a , —R 4a /—R 5a , —R 5a /—R 9a form a chemical bond;
optionally, one or more of the pairs —R 1 /—R 1a , —R 2 /—R 2a , —R 4 /—R 4a , —R 5 /—R 5a , —R 8 /—R 8a ,
—R 9 /—R 9a are joined together with the atom to which they are attached to form a C 3-10 cycloalkyl; or 3- to 10-membered heterocyclyl;
optionally, one or more of the pairs —R 1 /—R 4 , —R 1 /—R 5 , —R 1 /—R 6 , —R 1 /—R 7a , —R 4 /—R 5 , —R 4 /—R 6 , —R 8 /—R 9 , —R 2 /—R 3 are joined together with the atoms to which they are attached to form a ring A;
optionally, R 3 /R 3a are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle;
A is selected from the group consisting of phenyl; naphthyl; indenyl; indanyl; tetralinyl; C 3-10 cycloalkyl; 3- to 10-membered heterocyclyl; and 8- to 11-membered heterobicyclyl; and
wherein -L 1 - is substituted with -L 2 -Z or -L 2 -Z′ and wherein -L 1 - is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (II) is not replaced by -L 2 -Z or -L 2 -Z′ or a substituent;
wherein
-L 2 - is a single chemical bond or a spacer;
—Z is a water-soluble carrier; and
—Z′ is a water-insoluble carrier.
12 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11 , wherein —X— is —C(R 4 R 4a )— or —N(R 4 )—.
13 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11 , wherein —R 4 is substituted with -L 2 -Z or -L 2 -Z′.
14 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11 , wherein X 1 is C.
15 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11 , wherein ═X 3 is ═O.
16 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11 , wherein —X 2 — is —C(R 8 R 8a )—.
17 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11 , wherein —R 1 and —R 1a are —H.
18 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11 , wherein —R 2 and —R 2a are —H.
19 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11 , wherein —R 3 is —H and —R 3a is methyl.
20 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11 , wherein —R 4 and —R 4a are —H.
21 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 11 , wherein —R 8 and —R 8a are —H.
22 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein -L 2 - is selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y1 )—, —S(O) 2 N(R y1 )—, —S(O)N(R y1 )—, —S(O) 2 —, —S(O)—; —N(R′)S(O) 2 N(R y1a )—, —S—, —N(R y1 )—, —OC(OR y1 )(R y1a )—, —N(R y1 )C(O)N(R y1a )—, —OC(O)N(R y1 )—, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein -T-, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more —R y2 , which are the same or different and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y3 )—, —S(O) 2 N(R y3 )—, —S(O)N(R y3 )—, —S(O) 2 —, —S(O)—, —N(R y3 )S(O) 2 N(R y3a )—, —S—, —N(R y3 )—, —OC(OR y3 )(R y3a )—, —N(R y3 )C(O)N(R y3a )—, and —OC(O)N(R y3 )—;
—R y1 and —R y1a are independently of each other selected from the group consisting of —H, -T, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein -T, C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more —R y2 , which are the same or different, and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R y4 )—, —S(O) 2 N(R y4 )—, —S(O)N(R y4 )—, —S(O) 2 —, —S(O)—, —N(R y4 )S(O) 2 N(R y4a )—, —S—, —N(R y4 )—, —OC(OR y4 )(R y4a )—, —N(R y4 )C(O)N(R y4a )—, and —OC(O)N(R y4 )—;
each T is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each T is independently optionally substituted with one or more —R y2 , which are the same or different;
each —R y2 is independently selected from the group consisting of halogen, —CN, oxo (═O), —COOR y5 , —OR y5 , —C(O)R y5 , —C(O)N(R y5 R y5a ), —S(O) 2 N(R y5 R y5a ), —S(O)N(R y5 R y5a ), —S(O) 2 R y5 , —S(O)R y5 , —N(R y5 )S(O) 2 N(R y5a R y5b ), —SR y5 , —N(R y5 R y5a ), —NO 2 , —OC(O)R y5 , —N(R y5 )C(O)R y5a , —N(R y5 )S(O) 2 R y5a , —N(R y5 )S(O)R y5a , —N(R y5 )C(O)OR y5a , —N(R y5 )C(O)N(R y5a R y5b ), —OC(O)N(R y5 R y5a ), and C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and
each —R y3 , —R y3a , —R y4 , —R y4a , —R y5 , —R y5a and —R y5b is independently selected from the group consisting of —H, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.
23 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein -L 2 - is a C 1-20 alkyl chain, which is optionally interrupted by one or more groups independently selected from —O—, -T- and —C(O)N(R y1 )—; and which C 1-20 alkyl chain is optionally substituted with one or more groups independently selected from —OH, -T and —C(O)N(R y6 R y6a ); wherein —R y1 , —R y6 , —R y6a are independently selected from the group consisting of H and C 1-4 alkyl and wherein T is selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl.
24 . The CNP prodrug or a pharmaceutical acceptable salt thereof of claim 1 , wherein -L 2 - is of formula (i)
wherein
the dashed line marked with the asterisk indicates attachment to -L 1 -;
the unmarked dashed line indicates attachment to —Z or —Z′;
—R 1 is selected from the group consisting of —H, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 and 18; and
wherein the moiety of formula (i) is optionally further substituted.
25 . The prodrug or pharmaceutically acceptable salt thereof of claim 1 , wherein —Z has a molecular weight ranging from 5 to 200 kDa.
26 . The prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the carrier —Z comprises a C 8-24 alkyl or a polymer.
27 . The prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z comprises a polymer selected from the group consisting of 2-methacryloyl-oxyethyl phosphoyl cholins, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(alkyloxy) polymers, poly(amides), poly(amidoamines), poly(amino acids), poly(anhydrides), poly(aspartamides), poly(butyric acids), poly(glycolic acids), polybutylene terephthalates, poly(caprolactones), poly(carbonates), poly(cyanoacrylates), poly(dimethylacrylamides), poly(esters), poly(ethylenes), poly(ethyleneglycols), poly(ethylene oxides), poly(ethyl phosphates), poly(ethyloxazolines), poly(glycolic acids), poly(hydroxyethyl acrylates), poly(hydroxyethyl-oxazolines), poly(hydroxymethacrylates), poly(hydroxypropylmethacrylamides), poly(hydroxypropyl methacrylates), poly(hydroxypropyloxazolines), poly(iminocarbonates), poly(lactic acids), poly(lactic-co-glycolic acids), poly(methacrylamides), poly(methacrylates), poly(methyloxazolines), poly(organophosphazenes), poly(ortho esters), poly(oxazolines), poly(propylene glycols), poly(siloxanes), poly(urethanes), poly(vinyl alcohols), poly(vinyl amines), poly(vinylmethylethers), poly(vinylpyrrolidones), silicones, celluloses, carbomethyl celluloses, hydroxypropyl methylcelluloses, chitins, chitosans, dextrans, dextrins, gelatins, hyaluronic acids and derivatives, functionalized hyaluronic acids, mannans, pectins, rhamnogalacturonans, starches, hydroxyalkyl starches, hydroxyethyl starches and other carbohydrate-based polymers, xylans, and copolymers thereof.
28 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z is a branched polymer.
29 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z has a molecular weight of at least 10 kDa.
30 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z or —Z′ comprises a moiety
31 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z comprises a moiety of formula (a)
wherein
the dashed line indicates attachment to -L 2 - or to the remainder of —Z;
BP a is a branching point selected from the group consisting of —N<, —CR< and >C<;
—R is selected from the group consisting of —H and C 1-6 alkyl;
a is 0 if BP a is —N< or —CR< and n is 1 if BP a is >C<;
—S a —, —S a′ —, —S a″ — and —S a′″ — are independently of each other a chemical bond or are selected from the group consisting of C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more —R 1 , which are the same or different and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R 2 )—, —S(O) 2 N(R 2 )—, —S(O)N(R 2 )—, —S(O) 2 —, —S(O)—, —N(R 2 ) S(O) 2 N(R 2a )—, —S—, —N(R 2 )—, —OC(OR 2 )(R 2a )—, —N(R 2 )C(O)N(R 2a )—, and —OC(O)N(R 2 )—;
each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each -T- is independently optionally substituted with one or more —R 1 , which are the same or different;
each —R 1 is independently selected from the group consisting of halogen, —CN, oxo (═O), —COOR 3 , —OR 3 , —C(O)R 3 , —C(O)N(R 3 R 3a ), —S(O) 2 N(R 3 R 3a ), —S(O)N(R 3 R 3a ), —S(O) 2 R 3 , —S(O)R 3 , —N(R 3 )S(O) 2 N(R 3a R 3b ), —SR 3 , —N(R 3 R 3a ), —NO 2 , —OC(O)R 3 , —N(R 3 )C(O)R 3a , —N(R 3 )S(O) 2 R 3a , —N(R 3 )S(O)R 3a , —N(R 3 )C(O)OR 3a , —N(R 3 )C(O)N(R 3a R 3b ), —OC(O)N(R 3 R 3a ), and C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
each —R 2 , —R 2a , —R 3 , —R 3a and —R 3b is independently selected from the group consisting of —H, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different; and
—P a′ , —P a″ and —P a′″ are independently a polymeric moiety.
32 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z is of formula (d)
wherein
the dashed line indicates attachment to -L 2 -;
—Z b — is selected from the group consisting of C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more —R 1 , which are the same or different and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R 2 )—, —S(O) 2 N(R 2 )—, —S(O)N(R 2 )—, —S(O) 2 —, —S(O)—, —N(R 2 )S(O) 2 N(R 2a )—, —S—, —N(R 2 )—, —OC(OR 2 )(R 2a )—, —N(R 2 )C(O)N(R 2a )—, and —OC(O)N(R 2 )—;
each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each -T- is independently optionally substituted with one or more —R 1 , which are the same or different;
each —R 1 is independently selected from the group consisting of halogen, —CN, oxo (═O), —COOR 3 , —OR 3 , —C(O)R 3 , —C(O)N(R 3 R 3a ), —S(O) 2 N(R 3 R 3a ), —S(O)N(R 3 R 3a ), —S(O) 2 R 3 , —S(O)R 3 , —N(R 3 )S(O) 2 N(R 3a R 3b ), —SR 3 , —N(R 3 R 3a ), —NO 2 , —OC(O)R 3 , —N(R 3 )C(O)R 3a , —N(R 3 )S(O) 2 R 3a , —N(R 3 )S(O)R 3a , —N(R 3 )C(O)OR 3a , —N(R 3 )C(O)N(R 3a R 3b ), —OC(O)N(R 3 R 3a ), and C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
each —R 2 , —R 2a , —R 3 , —R 3a and —R 3b is independently selected from the group consisting of —H, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
and
—Z a is
wherein
BP a , —S a —, —S a′ —, —S ″ —, —S a′″ —, —P a′ , —P a″ , —P a′″ and a are used as defined in claim 31 .
33 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z is of formula (e)
wherein
the dashed line indicates attachment to -L 2 -;
e is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15; and
—Z a is
wherein
b1 is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7 and 8;
b2 is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8;
b3 is an integer ranging from and including 150 to 1000; and
b4 is an integer ranging from and including 150 to 1000.
34 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 33 , wherein e is 5, b1 is 2, b2 is 3 and b3 and b4 are both about 450.
35 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z is of formula (f)
wherein
the dashed line indicates attachment to -L 2 -;
BP f is a branching point selected from the group consisting of —N<, —CR< and >C<;
—R is selected from the group consisting of —H and C 1-6 alkyl;
f is 0 if BP f is —N< or —CR< and f is 1 if BP f is >C<;
—S f —, —S f′ —, —S f″ — and —S f′″ — are independently either a chemical bond or are independently selected from the group consisting of C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more —R 1 , which are the same or different and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R 2 )—, —S(O) 2 N(R 2 )—, —S(O)N(R 2 )—, —S(O) 2 —, —S(O)—, —N(R 2 )S(O) 2 N(R 2a )—, —S—, —N(R 2 )—, —OC(OR 2 )(R 2a )—, —N(R 2 )C(O)N(R 2a )—, and —OC(O)N(R 2 )—;
each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each -T- is independently optionally substituted with one or more —R 1 , which are the same or different;
each R 1 is independently selected from the group consisting of halogen, —CN, oxo (═O), —COOR 3 , —OR 3 , —C(O)R 3 , —C(O)N(R 3 R 3a ), —S(O) 2 N(R 3 R 3a ), —S(O)N(R 3 R 3a ), —S(O) 2 R 3 , —S(O)R 3 , —N(R 3 )S(O) 2 N(R 3a R 3b ), —SR 3 , —N(R 3 R 3a ), —NO 2 , —OC(O)R 3 , —N(R 3 )C(O)R 3a , —N(R 3 )S(O) 2 R 3a , —N(R 3 )S(O)R 3a , —N(R 3 )C(O)OR 3a , —N(R 3 )C(O)N(R 3a R 3b ), —OC(O)N(R 3 R 3a ), and C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
each —R 2 , —R 2a , —R 3 , —R 3a and —R 3b is independently selected from the group consisting of —H, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
and
—Z a′ , —Z a″ and —Z a′″ are independently
wherein
BP a , —S a —, —S a′ —, —S a″ —, —S a′″ —, —P a′ , —P a″ , —P a′″ and a are used as defined in claim 31 .
36 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z is of formula (g)
wherein
the dashed line indicates attachment to -L 2 -;
—S g —, —S g′ — and —S g″ — are independently selected from the group consisting of C 1-10 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl; wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally substituted with one or more —R 1 , which are the same or different and wherein C 1-50 alkyl, C 2-50 alkenyl, and C 2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T-, —C(O)O—, —O—, —C(O)—, —C(O)N(R 2 )—, —S(O) 2 N(R 2 )—, —S(O)N(R 2 )—, —S(O) 2 —, —S(O)—, —N(R 2 )S(O) 2 N(R 2a )—, —S—, —N(R 2 )—, —OC(OR 2 )(R 2a )—, —N(R 2 )C(O)N(R 2a )—, and —OC(O)N(R 2 )—;
each -T- is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl, 8- to 11-membered heterobicyclyl, 8- to 30-membered carbopolycyclyl, and 8- to 30-membered heteropolycyclyl; wherein each -T- is independently optionally substituted with one or more —R 1 , which are the same or different;
each R 1 is independently selected from the group consisting of halogen, —CN, oxo (═O), —COOR 3 , —OR 3 , —C(O)R 3 , —C(O)N(R 3 R 3a ), —S(O) 2 N(R 3 R 3a ), —S(O)N(R 3 R 3a ), —S(O) 2 R 3 , —S(O)R 3 , —N(R 3 )S(O) 2 N(R 3a R 3b ), —SR 3 , —N(R 3 R 3a ), —NO 2 , —OC(O)R 3 , —N(R 3 )C(O)R 3a , —N(R 3 )S(O) 2 R 3a , —N(R 3 )S(O)R 3a , —N(R 3 )C(O)OR 3a , —N(R 3 )C(O)N(R 3a R 3b ), —OC(O)N(R 3 R 3a ), and C 1-6 alkyl; wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
each —R 2 , —R 2a , —R 3 , —R 3a and —R 3b is independently selected from the group consisting of —H, and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
and
—Z a and —Z a′ are independently
wherein
BP a , —S a —, —S a′ —, —S a″ —, —P a′ , —P a″ , —P a′″ and a are used as defined in claim 31 .
37 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein —Z is of formula (h)
wherein
the dashed line indicates attachment to -L 2 -; and
each —Z c is a moiety
wherein
each c1 is an integer independently ranging from about 200 to 250.
38 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the CNP prodrug is of formula (IIe)
wherein
the unmarked dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to a moiety
wherein
each c1 is an integer independently ranging from 400 to 500.
39 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the CNP prodrug is of formula (IIe′)
wherein
the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to a moiety
wherein
each c1 is an integer independently ranging from 400 to 500.
40 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the CNP prodrug is of formula (IIe-i′)
wherein
the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to a moiety
wherein
each c1 is an integer independently ranging from 400 to 500.
41 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the CNP prodrug is of formula (IIe-ii′)
wherein
the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to a moiety
wherein
each c1 is an integer independently ranging from 400 to 500.
42 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the CNP prodrug is of formula (IIf)
wherein
the unmarked dashed line indicates the attachment to a nitrogen of -D which is a CNP moiety by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to —Z having the structure
wherein
each —Z a is
wherein
each c1 is an integer independently ranging from 200 to 250.
43 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the CNP prodrug is of formula (IIf′)
wherein
the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to —Z having the structure
wherein
each Z a is
wherein
each c1 is an integer independently ranging from 200 to 250.
44 . The CNP prodrug or a pharmaceutically acceptable salt thereof of claim 1 , wherein the CNP prodrug is of formula (IIf-i′)
wherein
the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to —Z having the structure
wherein
each Z a is
wherein
each c1 is an integer independently ranging from 200 to 250.
45 . The CNP prodrug or a pharmaceutically acceptable salt thereof of anyone claim 1 , wherein the CNP prodrug is of formula (IIf-ii′)
wherein
the unmarked dashed line indicates the attachment to a nitrogen provided by the side chain of the lysine at position 26 of the CNP moiety of SEQ ID NO:24 by forming an amide bond; and
the dashed line marked with the asterisk indicates attachment to —Z having the structure
wherein
each Z a is
wherein
each c1 is an integer independently ranging from 200 to 250.
46 . The prodrug or pharmaceutically acceptable salt thereof of claim 1 , wherein the residual activity of the CNP prodrug is less than 10%.
47 . A pharmaceutical composition comprising at least one CNP prodrug or pharmaceutically acceptable salt thereof of claim 1 and at least one excipient.
48 . The pharmaceutical composition of claim 47 , wherein the pharmaceutical composition has a pH ranging from and including pH 4 to pH 6.
49 . (canceled)
50 . A method of treating a patient suffering from a disease which can be treated with CNP comprising administering an effective amount of the prodrug or pharmaceutically acceptable salt thereof of claim 1 or a pharmaceutical composition comprising the prodrug or pharmaceutically acceptable salt thereof to the patient.
51 . The method of claim 50 , wherein the disease is selected from the group consisting of achondroplasia, hypochondroplasia, short stature, dwarfism, osteochondrodysplasias, thanatophoric dysplasia, osteogenesis imperfecta, achondrogenesis, chondrodysplasia punctata, homozygous achondroplasia, camptomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal type of osteogenesis imperfecta, short-rib polydactyly syndromes, rhizomelic type of chondrodysplasia punctata, Jansen-type metaphyseal dysplasia, spondyloepiphyseal dysplasia congenita, atelosteogenesis, diastrophic dysplasia, congenital short femur, Langer-type mesomelic dysplasia, Nievergelt-type mesomelic dysplasia, Robinow syndrome, Reinhardt syndrome, acrodysostosis, peripheral dysostosis, Kniest dysplasia, fibrochondrogenesis, Roberts syndrome, acromesomelic dysplasia, micromelia, Morquio syndrome, Kniest syndrome, metatrophic dysplasia, spondyloepimetaphyseal dysplasia, neurofibromatosis, Legius syndrome, LEOPARD syndrome, Noonan syndrome, hereditary gingival fibromatosis, neurofibromatosis type 1, Legius syndrome, cardiofaciocutaneous syndrome, Costello syndrome, SHOX deficiency, idiopathic short stature, growth hormone deficiency, osteoarthritis, cleidocranial dysostosis, craniosynostosis (e.g., Muenke syndrome, Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome, or Crouzonodermoskeletal syndrome), dactyly, brachydactyly, camptodactyly, polydactyly, syndactyly, dyssegmental dysplasia, enchondromatosis, fibrous dysplasia, hereditary multiple exostoses, hypophosphatemic rickets, Jaffe-Lichtenstein syndrome, Marfan syndrome, McCune-Albright syndrome, osteopetrosis and osteopoikilosis.
52 . The method of claim 50 , wherein the disease is an ophthalmic disorder.
53 . The method of claim 50 , wherein the disease is achondroplasia.
54 - 57 . (canceled)
58 . The method of claim 50 , wherein the step of administering the CNP prodrug or pharmaceutically acceptable salt thereof or the pharmaceutical composition is performed via topical, enteral or parenteral administration or by a methods of external application, injection or infusion, including intraarticular, periarticular, intradermal, subcutaneous, intramuscular, intravenous, intraosseous, intraperitoneal, intrathecal, intracapsular, intraorbital, intravitreal, intratympanic, intravesical, intracardiac, transtracheal, subcuticular, subcapsular, subarachnoid, intraspinal, intraventricular, intrasternal injection and infusion, direct delivery to the brain via implanted device allowing delivery of the invention or the like to brain tissue or brain fluid, direct intracerebroventricular injection or infusion, injection or infusion into brain or brain associated regions, injection into the subchoroidal space, retro-orbital injection or ocular instillation.
59 . The method of claim 53 wherein the administering step is performed via subcutaneous injection.Join the waitlist — get patent alerts
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